Discovery of gene variants associated with hypertension has been remarkably difficult, possibly because hypertension and blood pressure represent a complex interplay between initiating and compensating mechanisms. We propose that differences in the acute natriuretic responses to a saline load in young prehypertensive individuals will enable detection of genetic and hormonal/electrolyte associations with delayed excretion of the saline load which would be masked if studied under steady-state salt balance (or after compensatory mechanisms come into play). Selected neuro-humoral factors will be examined as potential intermediate phenotypes that predict delayed natriuretic responses. Once these salt-related genetic associations are uncovered by an acute saline challenge applied under controlled baseline conditions, we will test whether the identified gene variants are associated with hypertension in large multiracial and ethnic groups of subjects from the NHLBI Family Blood Pressure Program Study. It is proposed that deficiencies of acute hormonal or electrolyte responses to an acute saline load represent the earliest detectable initiating factors for salt-related hypertension, and that focusing on this intermediate phenotype will provide greater power than previously available in studies of hypertension or blood pressure, per se. The first group of subjects to be examined will be 480 Caucasians of Northern European descent from Utah. Acute saline infusions while on a low-salt diet (50 mmol/day) will elicit acute changes in hormones and electrolytes in pathways directly related to renal sodium excretion including the catecholamine-dopamine, renin-angiotensin-aldosterone, cortisol, and kallikrein systems. Hormone, electrolyte and water excretion, proximal and distal tubule reabsorption, and associated genetic polymorphisms will be analyzed by Bayesian pathway networks to model initial abnormal sodium responses and subsequent short-term compensation mechanisms. Candidate genes include those related to kidney control of salt and water excretion. Further, we will test whether the identified genetic associations with effectors or regulators of acute responses to sodium challenge are associated with hypertension in a separate, large, existing cross-sectional dataset (6,658 hypertensives and normotensives). The proposed systems and genetics approaches to acute sodium and volume changes under controlled baseline conditions, delayed sodium excretion and hypertension have not been previously studied. All other such studies have been on subjects in sodium balance or lack the systems and genetics approach. The resulting data together with the wealth of our existing data will provide an opportunity to test a new hypothesis about the initiating mechanisms that predict delayed sodium excretion. PUBLIC HEALTH RELEVANCE: This grant seeks to identify the primary abnormalities in humans that determine adverse blood pressure responses to high salt intake. Blood, urine, and DNA will be studied while individuals are infused with a sodium and water solution over a short period of time. Results may suggest better ways to prevent or to at least treat hypertension.